5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl
Upcoming SlideShare
Loading in...5
×
 

5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl

on

  • 1,296 views

 

Statistics

Views

Total Views
1,296
Views on SlideShare
766
Embed Views
530

Actions

Likes
0
Downloads
2
Comments
0

4 Embeds 530

http://www.chimeraresearchgroup.com 478
http://9www.chimeraresearchgroup.com 44
http://new.wpfix.org 6
http://translate.googleusercontent.com 2

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl 5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl Presentation Transcript

  • Understanding some basic trial designs in sarcomas (inclusive a placebo one) Winette van der Graaf Radboud University Medical Center Nijmegen, The Netherlands 22-11-12
  • The aim and value of clinical trials• Generating evidence for a treatment in a certain situation for a certain patient population• Evidence generated by clinical trials are the basis of guidelines (phase 3 studies generate the highest level evidence)• Often study results are extrapolated for “daily use”, but be aware: the study has been performed for a certain disease, in a defined patient population
  • A study population is not the same as the general population
  • Study patients should not only be the “athletes”
  • Age limits, but:
  • The incidence of soft tissue sarcomas
  • The incidence of soft tissue sarcomashas a peak around 65 years of age..
  • Old and fit...
  • Old and frail (co-medication, otherrelevant diseases!)
  • Also the disease varies a lot! Variation in:• Localisation primary tumor• Primary tumor plus or minus metastases• Histology: about 50 diagnoses• Location of metastases: lymph node, lung, liver, bone, etc• Symptoms• Q: If only metastases on X-ray and no symptoms: why should you treat a patient in a study?
  • Talk of today...trials designs..• From the very first clinical trial in sarcoma to three recent randomised phase 3 trials• With endpoint varying from response to progression free and overall survival
  • Phase of trials• Phase 1: first clinical trial in humans, aiming to establish the optimal dosage of a drug• Phase 2: efficacy of a new drug in a certain patient population• Phase 3: comparison of two treatment arms - blinded, if possible, or not
  • The first “mixed bag phase 2 trial”with adriamycin
  • The first efficacy trial with adriamycinin “sarcomas”
  • A Classical Phase 3 design• Standard treatment versus other standard treatmentOr• Standard treatment versus an experimental treatmentOr• Placebo versus new treatment
  • 3 Phase three trials• EORTC 62012- chemotherapy in STS - standard versus standard-• PALETTE EORTC 62072- pazopanib in STS - new versus placebo- no cross-over• GRID trial: regorafenib in GIST - new versus placebo- with cross-over
  • Results of a randomised phase III trial (EORTC 62012) of singleagent doxorubicin versus doxorubicin plus ifosfamide as firstline chemotherapy for patients with advanced, soft tissuesarcoma: a survival study by the EORTC Soft Tissue and BoneSarcoma Group. Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg- Thomas Hartmann, Patrick Schöffski, Jean-Yves Blay, Angelo Paolo dei Tos, Sandrine Marreaud, Saskia Litiere, Winette van der Graaf
  • PALETTE A randomized double blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy.An EORTC STBSG and GSK global network study (EORTC 62072) W. T. A. van der Graaf, J. Y. Blay, S. Chawla, D.W. Kim, B. Bui-Nguyen, P. Casali, P. Schoeffski, M. Aglietta, A. Staddon, Y. Beppu, A. Le Cesne, H. Gelderblom, I.Judson, N. Araki, M. Ouali, S. Marreaud, R A. Hodge, M. Dewji, P. Dei Tos, P. Hohenberger, on behalf of the global PALETTE study team.
  • Randomized Phase III Trial of Regorafenibin Patients (pts) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at least Imatinib (IM) and Sunitinib (SU): The GRID Trial GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki, P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida, D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators Demetri et al. ASCO 2012
  • Results of a randomised phase III trial (EORTC 62012) of singleagent doxorubicin versus doxorubicin plus ifosfamide as firstline chemotherapy for patients with advanced, soft tissuesarcoma: a survival study by the EORTC Soft Tissue and BoneSarcoma Group. Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg- Thomas Hartmann, Patrick Schöffski, Jean-Yves Blay, Angelo Paolo dei Tos, Sandrine Marreaud, Saskia Litiere, Winette van der Graaf
  • Rationale of the study• The outcome of patients with soft tissue sarcomas with locally advanced unresectable primary tumors and/or metastatic disease is poor.• Systemic treatment is usually given in this situation with a palliative intent, but has toxicity.• There is (transatlantic) debate about the best first-line treatment in this situation: single agent doxorubicin or a combination of doxorubicin and ifosfamide 21
  • Rationale of the study (II)Which situation justifies which treatment, especially themore toxic combination treatment?And in designing studies with new drugs/treatments:what will be the standard treatment arm to comparewith? 22
  • The designStratification:•Age (<50 vs ≥50)•PS (0 vs 1)•Liver metastases (0 vs +)•Histological grade (2 vs 3) Doxorubicin 75 mg/m2 d 1 or as a 72 hour continous i.v. infusion R Doxorubicin 25 mg/m2 d 1-3 New Treatment: B + Ifosfamide 2.5 g/m2 d 1-4 + Neulasta 6mg s.c. d5
  • End-points of the study The primary end point:overall-survival The secondary end points:response (RECIST)toxicity (CTC 2.0)treatment related mortality 24
  • Study statusAccrual:• 455 patients entered the study• 38 centers in 9 countries• Start: 4-2003 (start EORTC), 5-2008 (NCIC- 13 patients) »7 YEARS IS LONG, WHY?• Study Closure: 5-2010Clinical cut-off• 5-7-2012• Median follow-up: 56 months 25
  • Patient characteristics Treatment Doxo Doxo-Ifos Total (n=228) (n=227) (n=455) n (%) n (%) n (%)Age group < 40 yrs 52 (22.8) 60 (26.4) 112 (24.6) 40-49 yrs 78 (34.2) 70 (30.8) 148 (32.5) ≥ 50 yrs 98 (43.0) 97 (42.7) 195 (42.9)Age (years) Median 48 47 48 Range 18 - 60 18 - 63 18 - 63Gender Male 103 (45.2) 114 (50.2) 217 (47.7) Female 125 (54.8) 113 (49.8) 238 (52.3)Performance status 0 129 (56.6) 123 (54.2) 252 (55.4) 1 98 (43.0) 103 (45.4) 201 (44.2) 2 1 (0.4) 1 (0.4) 2 (0.4) 26
  • Overall survival 100 90 80 HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = 0.076 70 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment188 228 113 54 29 19 14 9 2 Doxo184 227 130 64 30 20 13 7 3 DxIf 27
  • Median overall survival:• Doxorubicin: 12.8 months (95.5 CI 10.5-14.3)• Doxorubicin-ifosfamide: 14.3 months (95.5% CI 12.5-16.5).Survival at 1-year:• Doxorubicin: 51% (95.5% CI 44-58)• Doxorubicin-ifosfamide: 60% (95.5% CI 53-66) 28
  • Overall survival 29
  • Progression free survival 100 90 80 HR = 0.74 (95% CI 0.60 – 0.90) 70 Stratified logrank test, p = 0.003 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment215 228 38 15 8 6 5 4 1 Doxo210 227 50 16 12 11 10 7 3 DxIf 30
  • Median PFSMedian PFS in the doxorubicin arm: 4.6 months (95% CI 2.9 – 5.6),in the combination arm 7.4 months (95% CI 6.6 – 8.3). 31
  • Progression free survival 32
  • Best overall response Treatment Doxo Doxo-Ifos Total (n=228) (n=227) (n=455) n (%) n (%) n (%)Complete Response 1 (0.4) 4 (1.8) 5 (1.1)Partial Response 30 (13.2) 56 (24.7) 86 (18.9) ORR 13.6 26.5No Change 105 (46.1) 114 (50.2) 219 (48.1)Progressive Disease 74 (32.5) 30 (13.2) 104 (22.9)Early Death - Progression 4 (1.8) 5 (2.2) 9 (2.0)Early Death – Other cause 3 (1.3) 2 (0.9) 5 (1.1)Significant difference between the two arms: p < 0.001(7.0)Not evaluable 11 (4.8) 16 27 (5.9) 33
  • Adverse events (grade ≥ 3) Doxo DxIf Total (N = 223) (N = 224) (N = 447)Neutropenia 37.2% 41.5% 39.4%Leucopenia 17.9% 43.3% 30.7%Febrile neutropenia 13.5% 45.9% 29.8%Anemia 4.6% 34.9% 19.7%Thrombocytopenia 0.4% 33.5% 17.0% 34
  • Treatment Doxo DxIf (N=215) (N=210) N (%) N (%)Post protocol Surgery 44 (20.5) 43 (20.5)treatment Radiotherapy 69 (32.1) 83 (39.5) Chemotherapy 136 (63.3) 134 (63.8) Doxorubicin 12 (5.6) 27 (12.9) Analog 3 (1.4) 1 (0.5) Ifosfamide 99 (46.0) 32 (15.2) Analog 6 (2.8) 13 (6.2) Trabectedin 33 (15.3) 37 (17.6) Docetaxel 25 (11.6) 34 (16.2) Analog 5 (2.3) 6 (2.9) Gemcitabine 32 (14.9) 40 (19.0) Dacarbazine 7 (3.3) 18 (8.6) Analog 0 (0.0) 1 (0.5) Pazopanib 14 (6.5) 14 (6.7) Eribulin 7 (3.3) 11 (5.2) Etoposide 8 (3.7) 11 (5.2) 35
  • Conclusions In this group of patients all below 60, median age 48 yearsThe combination of doxorubicin and ifosfamide:o doubled the response rateo improved PFS significantlyo it did not significantly improve survivalo It was considerably more toxic than doxorubicin alone. 36
  • This study supports personalised medicine in daily practice...• The standard treatment in the palliative setting remains single agent doxorubicin• If surgery for unresectable tumors or curative metastasectomy is considered, combination therapy gives the highest chance of response• In highly symptomatic disease in patients without co- morbidity combination treatment is optional and pro’s and cons should – as always- be discussed with the patient.• ….and since we have the results of this study, these discussions can be more balanced than before. 37
  • PALETTE A randomized double blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy.An EORTC STBSG and GSK global network study (EORTC 62072) W. T. A. van der Graaf, J. Y. Blay, S. Chawla, D.W. Kim, B. Bui-Nguyen, P. Casali, P. Schoeffski, M. Aglietta, A. Staddon, Y. Beppu, A. Le Cesne, H. Gelderblom, I.Judson, N. Araki, M. Ouali, S. Marreaud, R A. Hodge, M. Dewji, P. Dei Tos, P. Hohenberger, on behalf of the global PALETTE study team.
  • Background• Pazopanib: A multikinase angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit• In a prior phase 2 study of pazopanib in patients with advanced STS positive effect of pazopanib (PFR at 12 weeks):  44% in leiomyosarcoma  49% in synovial sarcoma  39% in other STS types• Insufficient activity in liposarcomas• Acceptable toxicity
  • Phase III Study Design 10 20 Pazopanib*(800mg QD) Endpoint Endpoints Stratification factors R (N = 246)  Performance status A N (0 vs 1) D OS ORRN= 369 O 2:1 PFS QoL  Number of prior lines of (RECIST v1.0) M Safety systemic therapy for I advanced disease Matching Placebo S (0/1 vs 2+) (N = 123) E Followed for survival Disease assessment at week 4-8-12-20 and at 8 week intervals thereafter * Until disease progression, unacceptable toxicity, withdrawal of consent for any reason, or death
  • Main Inclusion Criteria• Patients ≥18 years, WHO PS 0-1• Progressive disease before start of PALETTE study• Prior doxorubicine and a maximum of four lines of prior treatment for advanced disease (no more than 2 combination regimens)• Measurable disease on X-rays• No prior pazopanib or other angiogenesis inhibitors• Adequate organ function• No problems of hypertension, bleeding and/or brain metastases
  • STS included Histology• Included: strata: leio, synovial, other: • Fibroblastic • MPNST • Fibrohistiocytic • NOS • Leiomyosarcoma • Vascular STS • Synovial sarcoma • Malignant glomus tumors• But not: • liposarcoma • GIST • etc.
  • Study Status• Accrual  369 randomized patients over 17 months: FASTER THAN EXPECTED, DESPITE PLACEBO DESIGN WITHOUT CROSS-OVER!  4 continents, 13 countries, 72 institutions  EORTC: 45% - Other institutions: 55%
  • Who entered the study? Placebo (N=123) Pazopanib (N=246) Median (years) 51.9 56.7Age Range (years) 18.8 - 78.6 20.1 - 83.7 0 (WHO) 56 (46%) 113 (46%)Performance 1 (WHO) 67 (55%) 133 (54%) Leiomyosarcoma 50 (41%) 115 (47%)Histology (local) Synovial sarcoma 14 (11%) 30 (12%) Other type 59 (48%) 101 (41%) I / low 3 (2%) 24 (10%)Grade at initial II / intermediate 30 (24%) 63 (26%)diagnosis (local) III / high 90 (73%) 159 (65%)
  • Principal prior drug therapies Placebo (N=123) Pazopanib (N=246)Prior (neo)adjuvant therapy 36 (29%) 58 (24%)Prior systemic therapy for advanced 110 (89%) 232 (94%)disease 0-1 line 52 (42%) 110 (45%) 2-4 lines 71 (58%) 136 (55%)Including Anthracycline(s) 121 (98%) 243 (99%) Ifosfamide 93 (76%) 164 (67%) Gemcitabine 42 (34%) 85 (35%) Docetaxel 35 (29%) 69 (28%) Trabectedin 22 (18%) 38 (15%) Dacarbazine 19 (15%) 38 (15%) mTOR inhibitor(s) 6 (5%) 16 (7%)
  • RESULTS: Primary end-point Progression Free Survival (%) 100 90 Placebo Pazopanib 80 Median (months) 1.5 4.6 70 HazardWald test stratified : p<0.0001 0.31 ratio 1 95% CI (0.24,0.40) 60Percent P-value < 0.0001 50 40 30 20 10 0 (months) 0 6 12 Time 18 24 O N Number of patients at risk : Treatment arm 106 123 6 0 0 Placebo 168 246 63 12 1 Pazopanib
  • PFS by HistologyConsistent benefit in PFS across all 3 strata n (%) HR CI P-value Overall 369 (100%) 0.31 0.24-0.40 <0.0001 Leiomyosarcoma 158 (43%) 0.31 0.20-0.47 <0.0001 Synovial 38 (10%) 0.19 0.23-0.60 0.0002 other STS 173 (47%) 0.36 0.25-0.52 <0.0001
  • Interim Overall Survival (%) Placebo Pazopanib Median (months) 10.7 12.5 100 Hazard ratio 0.86 1 90 95% CI (0.67,1.11) 80 P-value 0.25 70 60Percent 50 40 30 20 10 0 (months) 0 6 12 Time 18 24 O N Number of patients at risk : Treatment arm 78 123 86 36 12 Placebo 137 246 184 83 23 Pazopanib
  • Best Overall Response based on the independent review Placebo (N=123) Pazopanib (N=239)Partial response 0 (0%) 14 (6%)Stable disease 47 (38%) 164 (67%)Progression 70 (57%) 57 (23%)Early death (progression) 6 (5%) 2 (1%)Early death (other cause) 0 (0%) 1 (0.4%)Unevaluable 0 (0%) 8 (3%)
  • Selected on-therapy Adverse Events Placebo (N=123) Pazopanib (N=239) Common Adverse Events All Grades Gr3 Gr4 All Grades Gr3 Gr4 Fatigue 60 (49%) 6 (5%) 1 (1%) 155 (65%) 30 (13%) 1 (0.4%) Diarrhea 20 (16%) 1 (1) 0 138 (58%) 11 (5%) 0 Nausea 34 (28%) 2 (2%) 0 129 (54%) 8 (3%) 0 Weight loss 25 (20%) 0 0 115 (48%) 0 0 Hypertension 8 (7%) 4 (3%) 0 99 (41%) 16 (7%) 0 Anorexia 24 (20%) 0 0 95 (40%) 14 (6%) 0 Hypopigmentation hair 3 (2%) 0 0 92 (39%) 0 0 Vomiting 14 (11%) 1 (1%) 0 80 (34%) 8 (3%) 0 Dysgeusia 5 (4%) 0 0 64 (27%) 0 0 Rash/desquamation 13 (11%) 0 0 43(18%) 1 (0.4%) 0 Mucositis 4 (3%) 0 0 29 (12%) 3 (1%) 0 Adverse Events of InterestMyocardial Dysfunction* 6 (5%) - - 21 (9%) 3 (1%) 1 (<1%)Venous thromboembolic** 3 (2%) 1 (<1%) 2 (1%) 13 (5%) 5 (2%) 1 (<1%)Pneumothorax - - - 8 (3%) - 1 (<1%) * Grouping of MedDRA Terms including LV dysfunction, cardiac failure, restrictive cardiomyopathy, pulmonary edema ** 2 subjects with venous thromboembolic events died of pulmonary embolus
  • Selected on-therapy Adverse Events Placebo (N=123) Pazopanib (N=239) STS Pazo renal Common Adverse Events All Grades Gr3 and 4 All Grades Gr3 and 4 All grades Fatigue 60 (49%) 7 (6%) 155 (65%) 31 (13%) 19% Diarrhea 20 (16%) 1 (1) 138 (58%) 11 (5%) 52% Nausea 34 (28%) 2 (2%) 129 (54%) 8 (3%) 26% Weight loss 25 (20%) 0 115 (48%) 0 Hypertension 8 (7%) 4 (3%) 99 (41%) 16 (7%) 40% Anorexia 24 (20%) 0 95 (40%) 14 (6%) 22% Hypopigmentation hair 3 (2%) 0 92 (39%) 0 38% Vomiting 14 (11%) 1 (1%) 80 (34%) 8 (3%) 21% Dysgeusia 5 (4%) 0 64 (27%) 0 Rash/desquamation 13 (11%) 0 43(18%) 1 (0.4%) Mucositis 4 (3%) 0 29 (12%) 3 (1%) Adverse Events of InterestMyocardial Dysfunction* 6 (5%) - - 21 (9%) 3 (1%) 1 (<1%)Venous thromboembolic** 3 (2%) 1 (<1%) 2 13 (5%) 5 (2%) 1 (<1%) (1% ) * Grouping of MedDRA Terms including LV dysfunction, cardiac failure, restrictive cardiomyopathy, pulmonary edemaPneumothorax - - - ** 2 subjects with venous thromboembolic events died of pulmonary embolus 8 (3%) - 1 (<1%)
  • Principal post-protocol Therapies WAS IT REAL LAST RESORT THERAPY? Placebo (N=122) Pazopanib (N=228)Radiotherapy 28 (23%) 36 (16%)Surgery 8 (7%) 16 (7%) Trabectedin 37 (30%) 53 (23%) Gemcitabine 24 (20%) 33 (15%) Ifosfamide 15 (12%) 13 (6%) Docetaxel 13 (11%) 17 (8%)Medical Dacarbazine 14 (12%) 12 (5%)Treatment Etoposide 9 (7%) 14 (6%) Anthracycline(s) 8 (7%) 10 (4%) Pazopanib 4 (3%) 4 (2%) Sorafenib 7 (6%) 6 (3%)
  • Conclusions• Pazopanib is an active drug in anthracycline pretreated metastatic soft tissue sarcoma patients.  : a 3-fold increase in PFS as compared to placebo! 3 months, is this worthwhile? The overall survival is not statistically significant better. WHY?
  • Randomized Phase III Trial of Regorafenibin Patients (pts) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at least Imatinib (IM) and Sunitinib (SU): The GRID Trial GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki, P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida, D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators Demetri et al. ASCO 2012
  • GIST – Regorafenib In Progressive Disease(GRID): Study Design Regorafenib + best supportive care Metastatic/ R (BSC) unresectable A 160 mg once daily Disease N 3 weeks on, O GIST pts D progression progressing O 1 week off (n=133) per independent Fdespite at least M 2:1 blinded central review F I prior imatinib ZA and sunitinib TI T O Placebo + BSC Unblinding R (n=236 screened; N Crossover offered forn=199 randomized) 3 weeks on, E placebo arm or 1 week off (n=66) A continued regorafenib for treatment arm T M• Multicenter, randomized, double-blind, E placebo-controlled phase III study Regorafenib N (unblinded)  Global trial: 17 countries across Europe, until next progression T North America, and Asia-Pacific  Stratification: treatment line (2 vs >2 prior lines), geographical location (Asia vs “Rest of World”) Demetri et al. ASCO 2012
  • GRID Study: Endpoints• Primary Endpoint: Progression-Free Survival (PFS)• Secondary Endpoints:  Overall survival  And others Demetri et al. ASCO 2012
  • GRID Study: Progression-Free Survival (primaryendpoint per blinded central review) Regorafenib significantly improved PFS vs placebo (p<0.0001); Demetri et al. ASCO 2012 primary endpoint met
  • GRID Study: Overall Survival (following 85% cross-over of patients on placebo arm)Because of the crossover design, lack of statistical significance between regorafenib and placebo was not unexpected Demetri et al. ASCO 2012
  • Disease Control and Overall Response Rates Regorafenib (N=133) Placebo (N=66) n (%) n (%)Disease control rate 70 (52.6) 6 (9.1)CR + PR + durable SD (≥12wks)Objective response rate 6 (4.5) 1 (1.5) Complete response 0 (0.0) 0 (0.0) Partial response 6 (4.5) 1 (1.5) Stable disease 95 (71.4) 22 (33.3) (at any time) Progressive disease 28 (21.1) 42 (63.6)Responses based on modified RECIST v1.1 Regorafenib improved rates of disease control vs placebo Demetri et al. ASCO 2012
  • • GRID: NO overall survival benefit• But this was expected due to the cross-over design of this placebo-controlled study
  • CONCLUSIONS• Placebo controlled trials are offered if no standard treatment is avalailable• These studies don’t have problems in fast accrual in case new therapies are offered.• Cross-over to the experimental study arm (new treatment) is possible if overall survival is not the end-point of the study